It has been reported that the compound [formula (II)] [3-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl]-ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-α]pyrimidin-4-one; or IUPAC name: 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl}-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one; CAS Nr. 144598-75-4; MW 426.48; Paliperidone or 9-OH risperidone or 9-hydroxy risperidone] is a benzoisoxazole derivative and one of new generation antipsychotics. The compound [formula (II)] is a selective monoaminergic antagonist having unique properties, and has a high affinity to serotoninergic 5-HT2 receptor and dopamine D2 receptor. The compound [formula (II)] can also binds to α1-adrenergic receptor, and binds to histaminergic H1 receptor and α2-adrenoceptor with a relatively low affinity. The compound [formula (II)] does not bind to a cholinergic receptor. The compound [formula (II)] is a potent D2 antagonist and can improve positive symptoms of schizophrenia, but it may cause less motor function inhibition and catalepsy than classic antipsychotics. Its balanced antagonistic effects on serotonin and dopamine of central nervous system may reduce the possibility of occurrence of extra pyramidal side effects, and its therapeutic effects may be extended to negative symptoms and emotional symptoms of schizophrenia.
The compound [formula (II)] is a new generation of psychotropic relative to Risperidone. U.S. Food and Drug Administration approved the marketing of an oral sustained release formulation of the compound [formula (II)] (Invega) developed by JANSSEN Pharmaceuticals, Inc in December 2006 for the treatment of mental disorders. Since the hydroxyl group of the compound results in an increased hydrophilicity, the absorption rate via oral administration is reduced, and the absolute bioavailability of the compound is only 28%, which is far lower than that of Risperidone (at least 70%), so that the daily dosage of the compound increased significantly, which in turn lead to increase in the pre-system side effects of the possible unabsorbed drug. The long-chain fatty acid ester of the compound [formula (II)] was reported in WO99/25354, but it is metabolized very slowly to form the compound [formula (II)] in vivo and cannot rapidly achieve the effective therapeutic effects. In order to overcome the above drawbacks associated with the compound [formula (II)] and fatty acid esters thereof, a series of derivatives of the compound [formula (II)] (the compounds of formula (I)) were synthesized, used as prodrugs of the compound [formula (II)] and reduced by rapid metabolism in vivo to form the compound [formula (II)] upon being taken, thereby achieving therapeutic effects.
